This chapter is (barely) relevant to Section G8(iv) of the 2017 CICM Primary Syllabus, which asks the exam candidate to "understand the pharmacology of antiarrhythmic drugs". These are a favourite of the college. For a variety of fairly commonsense reasons, there is an emphasis on testing the trainee's understanding of these drugs, as they are at the same time common, powerful, dangerous, and often poorly understood. However, historical CICM examiner focus has been interestingly narrow:
Do you notice a trend here? There is clearly some thirst among the examiners for a) certain iodinated compounds and b) cardiac glycosides. Owing to this clearly preferential treatment, each of these drugs has been given a chapter of its own, all the better to be familiar with their properties. The other agents have been piled unceremoniously into the wastebasket chapter below, mainly because the topic of antiarrhythmic classification has only ever appeared in one SAQ. What follows is a merciless oversimplification of a fascinating topic, but even this is probably excessive, as the college clearly just wanted people to earn three marks by dumbly listing the Vaughan Williams classes.
Oh well:
- Vaughan Williams classification of antiarrhythmic agents:
- Class I: fast sodium channel blockers:
- Class Ia: prolong the action potential (eg. quinidine)
- Class Ib: shortens the action potential (eg. lignocaine)
- Class Ic: no effect on the action potential (eg. flecainide)
- Class II: Beta-blockers (eg. metoprolol)
- Class III: Potassium channel blockers (eg. sotalol and amiodarone)
- Class IV: calcium channel blockers (eg. verapamil and diltiazem)
- Antiarrhythmic effects and the agents that exert them:
- Reduction of pacemaker automaticity: agents which decrease the calcium currents in pacemaker cells, i.e. Class II and Class IV agents
- Reduction of abnormal automaticity: agents which decrease the membrane resting potential in ventricular myocytes, i.e. mainly Class II agents
- Reduction of early afterdepolarisations: agents which reduce the action potential and repolarisation duration, i.e. Class II and Ib agents
- Some agents actually increase early afterdepolarizations by delaying repolarisation
- These are the same agents that prolong the QT interval (i.e. Class Ia and Class III agents)
- Reduction of delayed afterdepolarisations:
- Agents which decrease the availability of intracellular calcium (i.e. Class II and IV agents)
- Agents which decrease the availability of intracellular sodium (i.e. Class I agents)
- Reduction of reentry currents:
- Agents which slow AV nodal conduction (i.e. adenosine, digoxin, Class II and Class IV agents)
- Agents which slow the velocity of conduction (i.e. Class Ia and Ic agents)
- Agents which increase the refractory period (i.e Class III, Ia and Ic agents)
Realistically, the revising exam candiate would find that the Part One entry contains all the essential information required to pass these SAQs. It also helps that it is presented in a highly condensed form, free from verbal greebles and nurnies. For something published in a respectable journal (i.e. one which you have to pay to get published in), one could use something like Capucci et al (1998). This probably represents some sort of maximum of what a normal exam candidate should be expected to absorb. On the other hand, for the reader with an infinite capacity for minute pharmacological detail, the 1998 report by Carmeliet & Mubagwa will satisfy even the hungriest brain parasites. It is 72 pages long, and dense like a neutron star.
For the purposes of studying for the CICM First part exam, there is really only one system. One might occasionally hear it being referred to as the "Vaughan and Williams" or "Vaughan-Williams" classification, which is, of course, inaccurate because it is named after Miles Vaughan Williams, the celebrated pharmacologist and ninety-year-old fitness guru. His classification system was first presented in April of 1970, at the Symposium on Cardiac Arrhythmias in Elsinore, Denmark (yes, that Elsinore). The original 826-page symposium is not available electronically, and the nearest physical copy lays 110km north of the author, at the University of Newcastle Auschmuty Library. Fortunately, five years later, it was incorporated into a textbook, through which archaeologists can discern its original shape.
- Class I: drugs which "interfere directly with depolarization", eg. quinidine
- Class II: drugs with "antisympathetic action", eg. beta-blockers
- Class III: drugs which "prolong the duration of the action potential", eg amiodarone
It seems like a possible fourth class was also being considered in 1975, as verapamil had recently appeared onto the scene and had clearly demonstrated antiarrhythmic properties. However, it was not formally added at this stage. In fact, like everything that gets incorporated into a textbook, this three-class system turned out to be extremely tenacious and remained basically unchanged well into the 1980s even as novel agents were developed and new physiology research had come to light. The next reassessment of the Vaughan Williams classification was his own (1984), where he rephrased the class definitions, added calcium channel blockers, and further subdivided Class I into Ia, Ib and Ic on clinical grounds:
- Class I: fast sodium channel blockers:
- Class Ia: prolong the action potential (eg. quinidine)
- Class Ib: shortens the action potential (eg. lignocaine)
- Class Ic: no effect on the action potential (eg. flecainide)
- Class II: Beta blockers (eg. metoprolol)
- Class III: Potassium channel blockers (eg. sotalol and amiodarone)
- Class IV: calcium channel blockers (eg. verapamil and diltiazem)
However, the modern reader will readily point out that not only do we have multiple other agents currently used to treat or prevent arrhythmias, but there are also many agents which were already well established in he 1980s (eg. digoxin) which seem to be unfairly omitted from this classification system. Moreover, many among the listed drugs have multiple effects across multiple classes (famously, amiodarone). In response to these shortcomings, Rosen & Schwartz (1991) offered to reclassify antiarrhythmic drugs without trying to pigeonhole them into limiting categories. They called their system "The Sicilian Gambit", in reference to an opening chess move which involves the sacrifice of pieces in order to achieve a strategic advantage. Confusingly, they called it "Sicilian" because the European Societ of Cardiology met in Sicily that year, and not because of the Sicilian defence which is another popular opening move. These random details notwithstanding, the authors had a rather noble purpose: to bring the classification of antiarrhythmics out of its Vaughn Williams disarray, and to present the agents in a spreadsheet which illustrates their multiple simultaneous effects, like so:
Unfortunately, judging by the limited acceptance of this schema, it appears that everybody else had preferred disarray. To illustrate how much this is the case, one is directed to the last entry into this saturated field, made by Lei et al (2018), on the centenary of M. Vaughan Williams' birth. Their system is well-reasoned, comprehensive, inclusive of all existing agents, and therefore unwieldy and awkward:
- Class 0: Sinoatrial node blockers
- Just one subclass, and one member - ivabradine
- Class I: voltage-gated sodium channel blockers
- Class Ia: intermediate-dissociating Na+ channel blockers, eg. quinidine
- Class Ib: fast-dissociating Na+ channel blockers, eg. lignocaine
- Class Ic: slow-dissociating Na+ channel blockers, eg. flecainide
- Class Id: late Na+ current blockers, eg. ranolazine
- Class II: Autonomic inhibitor and activators
- Class IIa: non-selective β-blockers, eg. propanolol
- Class IIb: non-selective β-agonists, eg. isoprenaline
- Class IIc: Muscarinic M2 receptor inhibitors, eg. atropine
- Class IId: Muscarinic M2 receptor agonists, eg. digoxin
- Class IIe: Adenosine A1 receptor agonists, eg. adenosine
- Class III: Potassium channel blockers and openers
- Class IIIa: nonselective K+ channel blockers, eg. amiodarone and sotalol
- Class IIIb: metabolically dependent K+ channel blockers, eg. nicorandil
- Class IIIc: transmitter dependent K+ channel blockers (none available)
- Class IV: Ca2+ handling modulators
- Class IVa: nonselective Ca2+ channel blockers (eg. verapamil and diltiazem)
- Class IVb: intracellular Ca2+ channel blockers (eg. flecainide, propafenone)
- Class IVc: sarcoplasmic reticular Ca2+ pump activators (none available)
- Class IVd: membrane Ca2+ exchange inhibitors (none available)
- Class IVe: Cytosolic Ca2+ handling protein phosphorylators (none)
- Class V: mechanosensitive channel blockers (none currently available)
- Class VI: gap junction channel blockers (none curently available)
- Class VII: upstream target modulators (ACE-inhibitors, statins, omega-3 fatty acids)
This system is reproduced here mainly because of the authors' fondness for awkward things, and in the hope that it one day finds more recognition than it currently has. One must remember that the official college textbook (and basically all the other influential material on this topic) were published before 2018 and will therefore be parroting the 1984 version of the Vaughan Williams classification. Moreover, many of the CICM Part I examiners will have trained during this time period and will have some nostalgic fondness for the old system. Therefore, the trainee is advised not to startle these people with any unnecessarily modern concepts. One should not present oneself as a dangerous radical anarchist during one's pharmacology viva. It is in this counterrevolutionary spirit that the rest of this discussion will be conducted.
Anyway. From the emphasis on mechanisms of action which is inherent in this classification system, it follows that the only logical way to systematically discuss these agents is to start with their pharmacodynamic properties, and to handle the boring pharmacokinetics as an afterthought and shadow. This would be fairly consistent with college expectations, as they really only ever seemed interested in the ADME of amiodarone and digoxin, and those are handled separately.
To paraphrase the entire chapter dealing with abnormal cardiac electrical activity, as well as Grant (1992) and Barrio-Lopez (2020), arrhythmias arise because of:
From this, it follows that antiarrhythmic effects should address these proarrhythmic mechanisms in some way. And indeed they do, but not in a way which makes them any easier to categorise. Many drugs with antiarrhythmic properties address several of these mechanisms simultaneously, and others may actually promote arrhythmias by prolonging repolarisation (those would be all the antiarrhythmics which prolong the QT interval). Still, it is possible to vaguely relate arrhythmogenic and antiarrhythmic mechanisms, as follows:
Now, for each class, some sort of short point-form summary of pharmacodynamic properties will be attempted, mainly in case one day these drugs become the topic of an SAQ. This has already happened to Class I agents in Question 9 from the second paper of 2012, which means that these are probably fair game.
In their comments to Question 9 from the second paper of 2012, the college had referred "an excellent table in Stoelting" as a way of describing what they wanted from a tabulated answer about the electrophysiological effects of Class 1 agents. That table is reproduced below, for easy reference:
The reader must be warned that this table comes with no explanations in the text of that book, nor any references to follow. Still it remains a major reference for the people that write CICM exams. From this, we can conclude that it is intended to be committed to memory, and not to be understood. That would be enough to pass the CICM First Part exam. However, most normal people will probably agree that knowledge is not defined by data storage, and having a grasp of the underlying principles probably has some value for the intensivist in training. Therefore, wherever possible, some of the sections that follow will go on deep tangents into the electrophysiological trickery that produces these antiarrhythmic effects listed in the Stoelting table.
Class I agents are sodium channel blockers. They generally bind to a site inside the pore of the Nav1.5 subunit of the fast voltage-gated sodium channel, which is responsible for Phase 0 of the cardiac action potential. All prefer to bind to open or inactivated sodium channels (though the slowly dissociating Class Ic agents remain bound even when the channels return to their resting state). Speaking of which, this class is further subdivided into subclasses according to what the drugs do to the action potential and what dissociation kinetics they have:
The antiarrhythmic effect is felt in multiple ways:
There is also a sub-classification of beta-blockers, one of which can be mentioned here:
Though most of the antiarrhythmic effect comes from their β1 effects, one needs to mention that some of these drugs have sodium channel blocker properties (propanolol) and others block potassium channels (sotalol). However, they do not need those effects. Beta blockade has a rather diverse and potent effect on multiple cardiac ion channels, as listed in this table paraphrased from Dorian (2005):
Ion channel | Effect of beta-blockade |
INa fast inward sodium current | Reduced current |
Ito early, transient inward (repolarising) potassium current; | Reduced current |
ICa,L L-type inward calcium current | Reduced current |
INa/Ca sodium/calcium exchange current | Reduced current |
Iti transient inward current | Reduced current |
IK1 inward rectifier potassium current | Increased current |
IKs slow delayed rectifier potassium current | Reduced current |
IKr rapid delayed rectifier potassium current | Increased current |
If pacemaker current (sodium) | Reduced current |
All of this is due to the downscaling of the intracellular cAMP-mediated signalling that results from beta blockers competing with catecholamines. According to the the table from Stoelting, the net electrophysiological effect of these ion channel current changes should be:
which, on the surface ECG, should translate into
How does any of this connect to the abovementioned ion channel effects? For a drug class which has been available for so many decades, the literature on the electrophysiological effects of beta blockers is surprisingly well hidden. Some material can be unearthed by dusting off studies like Venditti et al (1987), who reported on the empirical findings of animal experiments for different beta blocker agents. The original table of results is presented below. As you can see, the situation is a lot more complex than the Stoelting table will have you believe:
The weird lack of data for commonly used drugs like metoprolol, and the weird excess of data for rare exotic beta blockers like pindolol and nadolol, is due to the vintage of this study, which dates back to 1987 (with metoprolol only having entered the market in 1982). Still, you can make out that broad trends really don't seem to exist across this group (for example, to say that all beta blockers uniformly increase the duration of the action potential would be patently untrue). Things are not helped by the fact that the best studied beta blocker was propanolol, as it was discovered way back in 1965 - but it also happens to have a bunch of sodium blocker effects which makes it a poor subject for studying pure β1 antagonism. Things are definitely not helped by the fact that other studies produce totally contradictory fiundings, such as Sänchez-Chapula (1992) who looked at the effect of metoprolol on ventricular myocytes and found that it decreases the action potential duration.
Surely, by this point even the most loyal and patient reader will have sprayed profanities at their monitor, faced with this level of confusion and uncertainty. Who cares what happened to guinea pig myocytes in the eighties, they might ask. Tell me what CICM want me to write in my exam paper! Unfortunately, this absolutely reasonable request can only be answered with the Stoelting table. This is probably what the First Part Exam question-writers will be referring to when they put together the SAQs for the written paper. You can bet that they won't be leafing through yellowing copies of The American Journal of Cardiology from 1987. From this, it follows that Deranged Physiology would serve its readership best by trying to explain why the Stoelting table contains what it contains, and to find whatever evidence there is to support its assertions.
Thus:
So, how does all this affect arrhythmogenicity? In summary:
Amiodarone sotalol ibutilide and vernakalant are really the main contenders here, though worldwide there is an even larger selection of these agents available. This class prolongs repolarisation by interfering with the function of inward rectifier and outward delayed rectifier potassium currents, increasing the duration of the refractory period and of the action potential as a whole.
It is hard to discuss the Class III effects because the poster child for this class is amiodarone, and it acts promiscuously on all Class I-IV molecular targets. In fact, all Class III agents have some kind of extra weirdness (sotalol is a beta-blocker, ibutilide acts on slow inward depolarising sodium currents, etc). A "pure" potassium channel blocker effect is therefore difficult to describe using an example. Strictly speaking, they should only prolong repolarisation. The best resource to explain this would probably be the little fragment from Cardiac Electrophysiology: From Cell to Bedside (p. 518 of the 2017 edition). In short, these drugs mainly block Ikr, Iks and Ik1 currents which are responsible for Phase 3 of the cardiac action potential. Class III drugs are not unique in the effect, as there are many other drugs which interfere with this current (notably, macrolide antibiotics and antipsychotic drugs). One might say that some drugs prolong the QTc as an accidental side effect, but Class III agents do it intentionally. In the form of a diagram, one would express this like so:
So,
Verapamil and diltiazem are the only real representatives here, as these are non-selective agents, whereas the dihydropyridine subclass tends to only affect the calcium channels in the vascular smooth muscle. Walker & Chia (1989) offer a good summary of their antiarrhythmic effects. In brief, their main effects are on pacemaker tissue, and on Phase 2 of the cardiac action potential. The Stoelting table makes a number of statements about these drugs, which need to be memorised unquestioningly by CICM exam candidates, and should not be subjected to any further scrutiny.
In terms of their effects on arrhythmogenicity:
At risk of being seen to promote the apostate classification system by Lei et al (2018), one needs to tentatively recognise that there are other drugs out there (digoxin, magnesium, adenosine, etc) which do not fit neatly into the Vaughan Williams classification.
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